Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, Valencia, Spain.
Fundación IVI, IVI-RMA Global, Valencia, Spain.
Hum Reprod Update. 2022 Nov 2;28(6):798-837. doi: 10.1093/humupd/dmac025.
To provide the optimal milieu for implantation and fetal development, the female reproductive system must orchestrate uterine dynamics with the appropriate hormones produced by the ovaries. Mature oocytes may be fertilized in the fallopian tubes, and the resulting zygote is transported toward the uterus, where it can implant and continue developing. The cervix acts as a physical barrier to protect the fetus throughout pregnancy, and the vagina acts as a birth canal (involving uterine and cervix mechanisms) and facilitates copulation. Fertility can be compromised by pathologies that affect any of these organs or processes, and therefore, being able to accurately model them or restore their function is of paramount importance in applied and translational research. However, innate differences in human and animal model reproductive tracts, and the static nature of 2D cell/tissue culture techniques, necessitate continued research and development of dynamic and more complex in vitro platforms, ex vivo approaches and in vivo therapies to study and support reproductive biology. To meet this need, bioengineering is propelling the research on female reproduction into a new dimension through a wide range of potential applications and preclinical models, and the burgeoning number and variety of studies makes for a rapidly changing state of the field.
This review aims to summarize the mounting evidence on bioengineering strategies, platforms and therapies currently available and under development in the context of female reproductive medicine, in order to further understand female reproductive biology and provide new options for fertility restoration. Specifically, techniques used in, or for, the uterus (endometrium and myometrium), ovary, fallopian tubes, cervix and vagina will be discussed.
A systematic search of full-text articles available in PubMed and Embase databases was conducted to identify relevant studies published between January 2000 and September 2021. The search terms included: bioengineering, reproduction, artificial, biomaterial, microfluidic, bioprinting, organoid, hydrogel, scaffold, uterus, endometrium, ovary, fallopian tubes, oviduct, cervix, vagina, endometriosis, adenomyosis, uterine fibroids, chlamydia, Asherman's syndrome, intrauterine adhesions, uterine polyps, polycystic ovary syndrome and primary ovarian insufficiency. Additional studies were identified by manually searching the references of the selected articles and of complementary reviews. Eligibility criteria included original, rigorous and accessible peer-reviewed work, published in English, on female reproductive bioengineering techniques in preclinical (in vitro/in vivo/ex vivo) and/or clinical testing phases.
Out of the 10 390 records identified, 312 studies were included for systematic review. Owing to inconsistencies in the study measurements and designs, the findings were assessed qualitatively rather than by meta-analysis. Hydrogels and scaffolds were commonly applied in various bioengineering-related studies of the female reproductive tract. Emerging technologies, such as organoids and bioprinting, offered personalized diagnoses and alternative treatment options, respectively. Promising microfluidic systems combining various bioengineering approaches have also shown translational value.
The complexity of the molecular, endocrine and tissue-level interactions regulating female reproduction present challenges for bioengineering approaches to replace female reproductive organs. However, interdisciplinary work is providing valuable insight into the physicochemical properties necessary for reproductive biological processes to occur. Defining the landscape of reproductive bioengineering technologies currently available and under development for women can provide alternative models for toxicology/drug testing, ex vivo fertility options, clinical therapies and a basis for future organ regeneration studies.
为了为植入和胎儿发育提供最佳环境，女性生殖系统必须与卵巢产生的适当激素一起协调子宫动力学。成熟的卵子可以在输卵管中受精，然后受精卵被运送到子宫，在那里它可以着床并继续发育。宫颈充当物理屏障，保护胎儿在整个怀孕期间免受伤害，阴道充当产道（涉及子宫和宫颈机制）并促进交配。任何影响这些器官或过程的病理学都可能影响生育能力，因此，能够准确地对其进行建模或恢复其功能，对于应用和转化研究至关重要。然而，人类和动物模型生殖道的固有差异，以及二维细胞/组织培养技术的静态性质，需要继续研究和开发动态和更复杂的体外平台、离体方法和体内疗法，以研究和支持生殖生物学。为了满足这一需求，生物工程通过广泛的潜在应用和临床前模型，将女性生殖研究推向了一个新的维度，而不断涌现的大量和多样化的研究使得该领域的状况迅速变化。
本综述旨在总结当前在女性生殖医学背景下可用和正在开发的生物工程策略、平台和疗法方面的大量证据，以进一步了解女性生殖生物学并为生育能力恢复提供新的选择。具体来说，将讨论用于子宫（子宫内膜和子宫肌层）、卵巢、输卵管、宫颈和阴道的技术。
在 PubMed 和 Embase 数据库中对全文文章进行了系统搜索，以确定 2000 年 1 月至 2021 年 9 月期间发表的相关研究。搜索词包括：生物工程、生殖、人工、生物材料、微流控、生物打印、类器官、水凝胶、支架、子宫、子宫内膜、卵巢、输卵管、子宫颈、阴道、子宫内膜异位症、子宫腺肌病、子宫肌瘤、衣原体、Asherman 综合征、宫内粘连、子宫息肉、多囊卵巢综合征和原发性卵巢功能不全。通过手动搜索选定文章和补充评论的参考文献，还确定了其他研究。纳入标准包括原创性、严格性和可访问性的同行评审工作，以英语发表，涉及女性生殖生物工程技术的临床前（体外/体内/离体）和/或临床测试阶段。
在确定的 10390 条记录中，有 312 项研究被纳入系统评价。由于研究测量和设计的不一致，研究结果是定性评估的，而不是通过荟萃分析评估的。水凝胶和支架常用于各种与女性生殖道相关的生物工程研究。新兴技术，如类器官和生物打印，分别提供了个性化诊断和替代治疗选择。结合各种生物工程方法的有前途的微流控系统也显示出转化价值。
调节女性生殖的分子、内分泌和组织水平相互作用的复杂性给生物工程方法替代女性生殖器官带来了挑战。然而，跨学科工作正在为生殖生物学过程发生所需的理化性质提供有价值的见解。定义当前可用于女性的生殖生物工程技术的景观和正在开发中，可以为毒理学/药物测试、离体生育选择、临床治疗和未来器官再生研究提供替代模型。
